A JANUS KINASE INHIBITOR, JAB, IS AN INTERFERON-GAMMA-INDUCIBLE GENE AND CONFERS RESISTANCE TO INTERFERONS

It has been shown that interferons (IFNs) exert their signals through receptor-associated Janus kinases (JAKs) and signal transducers and ac tivators of transcription (STATs). However, molecular mechanism of reg ulation of IFN signaling has not been fully understood. We have report ed novel cytokine-inducible SH2 protein (CIS) and JAK binding protein (JAB) family genes that can potentially modulate cytokine signaling. H ere we report that JAB is strongly induced by IFN-gamma but not by IFN -beta in mouse myeloid leukemia M1 cells and NIH-3T3 fibroblasts. NIH- 3T3 cells ectopically expressing JAB but not CIS3 lost responsiveness to the antiviral effect of IFN-beta and IFN-gamma. M1 leukemic cells s tably expressing JAB were also resistant to IFN-gamma and IFN-beta-ind uced growth arrest. In both NIH-3T3 and M1 transformants expressing JA B, IFN-gamma did not induce tyrosine phosphorylation and DNA binding a ctivity of STAT1. Moreover, IFN-gamma-induced activation of JAK1 and J AK2 and IFN-beta-induced JAK1 and Tyk2 activation were inhibited in NI H-3T3 JAB transformants. These results suggest that JAB inhibits IFN s ignaling by blocking JAK activity. We also found that IFN-resistant cl ones derived from LoVo cells and Daudi cells expressed high levels of JAB without stimulation. In IFN-resistant Daudi cells, IFN-induced STA T1 and JAK phosphorylation was partially reduced. Therefore, overexpre ssion of JAB could be, at least in part, a mechanism of IFN resistance . (C) 1998 by The American Society of Hematology.